Prenyl transferase (1'-4 coupling) and squalene synthetase (1'-1 coupling) catalyze two important reactions in the sterol biosynthetic pathway. We will study the mechanisms of the 1'-4 and 1'-1 condensation reactions with substrate analogues whose reactivities differ from those of the natural substrates in a predictable manner. Fluorine-containing substrate analogues will be used to probe for the development of positive or negative charge during the course of the enzyme catalyzed reactions. The 1'-1 coupling reaction involves a complicated set of rearrangements as farnesyl pyrophosphate goes to presqualene pyrophosphate and on to squalene. Sulfur-containing substrate analogues will be prepared which can trap reactive intermediates during the rearrangement of presqualene pyrophosphate to squalene. The substrate analogues to be examined are potential, selective inhibitors of prenyl transferase and squalene synthetase, and thus, offer a possibility for regulating sterol metabolism at the branch point to dolichols and respiratory coenzymes. To date no such selective inhibitor exists.